KR102636936B1 - Highly concentrated formulation - Google Patents

Abstract

The present invention provides a high concentration formulation of cortexolone-17α-propionate suitable for treating alopecia.

Description

Highly concentrated formulation

Alopecia are a group of disorders with multiple and diverse etiologies that result in loss of hair from the body. The most common form of alopecia is androgenetic alopecia (“AGA”). AGA is also commonly called alopecia androgenetica, male pattern baldness, or male or female pattern hair loss. AGA is reported to occur in approximately 50% of men over 40 years of age. This form of alopecia can eventually affect up to 80% of white men and about half of all women by the age of 70. Hair loss is often a cause of great concern to patients for cosmetic and psychological reasons, but it can also be an important sign of systemic disease.

AGA is a hereditary hair follicle disease, which is also androgen-dependent. In particular, dihydrotestosterone plays a major role in the development and progression of AGA. Hair loss due to AGA is progressive, so patients with the disease experience a decrease in terminal-to-vellus hair ratio, typically 4:1, over time. During this process, the hair is converted to indeterminate hair and finally to down. Men present with hair thinning in the temporal region, which advances to the crown region as AGA progresses. Women usually have more diffuse thinning over the crown area, presenting the male pattern as a less common case.

In vivo , AGA is characterized by increased levels and activity of the 5α-reductase isoenzyme. This enzyme converts testosterone (T) to its active metabolite dihydrotestosterone (DHT). High concentrations of DHT at the hair-follicle level - due to the increased binding capacity of this hormone to hair follicle androgen receptors - shorten the hair cycle and gradually shrink scalp hair follicles. After hair follicles shrink, fibrous tracts remain. These DHT-dependent effects are believed to be reversible in most cases, making AGA amenable to medical treatment with drugs that can reduce DHT production or antagonize DHT/T interactions with hair follicle androgen receptors. There will be.

Current medical management of AGA includes surgical and pharmacological treatment options. The most common form of surgical intervention for AGA is hair transplantation. This procedure has been performed successfully for the past 40 years. Hair transplantation is performed by follicular unit strip surgery (FUSS) or follicular unit extraction (FUE), from intact hair follicles from within the safe donor area (SDA) of the patient's scalp. It involves collecting. Improvements to these procedures over the past decade have resulted in significantly improved hair survival and a more natural appearance.

Although the cosmetic results after surgery are often satisfactory, surgery can only be performed when a sufficient amount of donor plugs (or hair follicles) are available to cover the bald area(s). Additionally, hair transplants are generally used for patients who have experienced massive hair loss and for patients who have not yet developed AGA. For example, in younger patients, hair transplants are generally not recommended, as androgens, especially DHT, can act on the newly transplanted hair follicles, causing the same thinning and ultimately hair loss that occurred in the original hair follicles. Because there is. For this reason, pharmacological intervention is preferred at the onset of AGA and in the early stages.

Currently, only two pharmaceutical products are approved for the treatment of AGA: minoxidil (commercially sold as ROGAINE® and its generic forms) and finasteride (commercially sold as PROPECIA®). Minoxidil formulated as a topical drug product is currently available in two strength levels: 2% (topical solution) and 5% (as a topical solution or foam). To be effective, minoxidil needs to be converted to its active metabolite, minoxidil sulfate, by the enzyme sulfotransferase. This enzyme is present in the outer root sheath of growing hair follicles.

The exact mechanism by which minoxidil promotes hair growth is still unclear, but it is believed that minoxidil sulfate opens ATP-sensitive potassium channels in cell membranes, resulting in vasodilation. However, vasodilatation does not appear to be responsible for minoxidil-induced hair growth. Other possible effects of minoxidil on hair follicles include: a) increased expression of vascular endothelial growth factor (VEGF) mRNA in the dermal papilla, indicating that the drug induces angiogenesis in the dermal papilla; b) Activation of cytoprotective prostaglandin synthase-1, a cytoprotective enzyme that stimulates hair growth; and c) increased expression of hepatocyte growth factor (HGF), a hair growth promoting factor.

In various clinical trials, minoxidil was found to be effective in significantly improving total hair count and non-down hair count compared to placebo after 6 to 12 months of treatment. Moreover, minoxidil preparations are well tolerated and have only mild side effects. Despite these beneficial effects, minoxidil inhibits dihydrotestosterone (DHT), or 5-alpha reductase, the enzyme responsible for its accumulation around hair follicles - a major mediator of male pattern baldness in genetically susceptible individuals. does not reduce As a result, when treatment is stopped, DHT decreases and ultimately destroys genetically predisposed hair follicles.

Meanwhile, finasteride inhibits type II 5-alpha reductase, which is responsible for the conversion of testosterone to DHT in hair follicles. Finasteride is administered orally in 1 mg tablet form. A single oral dose of 1 mg of finasteride reduces not only serum DHT but also scalp DHT by up to 70% compared to baseline. In several published clinical trials, finasteride 1 mg was found to be effective in significantly improving total hair count compared to placebo after 6 months of treatment. The significant increase in total hair count in patients treated with finasteride 1 mg compared to placebo was maintained over long-term treatment (up to 60 months).

Although finasteride effectively halts hair loss and improves new hair growth, there are possible detrimental effects associated with its use. Above all, finasteride is contraindicated in women due to its suspected teratogenic effects. Therefore, women who are pregnant or may become pregnant, regardless of whether they suffer from AGA or not, are strongly warned to avoid contact with crushed or broken tablets. Additionally, because finasteride is distributed systemically, it reduces DHT levels not only in hair follicles but also in plasma. This systemic activity is responsible for finasteride's major side effects, which include decreased libido, erectile dysfunction (erectile dysfunction), ejaculatory dysfunction, and reduced ejaculate volume. Other less common side effects include breast swelling, palpitations, testicular pain, persistent decrease in libido after discontinuation, infertility, and depression.

Considering the deficiencies and shortcomings associated with finasteride and minoxidil therapy, it is clear that there is a need in the art for new methods and active agents to treat alopecia, particularly AGA.

1. Korean Patent Publication No. 10-2010-0044845 (2010.04.30.)

1. Celasco, Giuseppe, et al. “Biological profile of cortexolone 17a-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist.” Arzneimittelforschung 54.12: 881-886 (2004.)

Cortexolone-17α-propionate (17α-propionyloxy-21-hydroxy-pregna-4-en-3,20-dione) is known to prevent androgenic hormones from binding to their receptors. It is a topical antiandrogen. It is known to be suitable for treating acne, alopecia, and other diseases of the skin and skin appendages. See, for example, US Pat. Nos. 8,143,240 and 8,865,690. This compound is also known to exist in several distinct crystalline polymorphs, each of which has unique properties. See, for example, US Pat. No. 8,785,427. Each of these patents is incorporated herein by reference in its entirety.

Although certain formulations of cortexolone-17α-propionate have been disclosed in the art, such formulations have inherent solubility limitations of the active agent, and administration of higher concentrations, especially after repeated administrations, is limited to the active agent and/or It was limited to concentrations of less than 2% by weight due to concerns that it may result in greater and unwanted systemic exposure to its metabolites.

Despite these concerns, it has now been unexpectedly discovered that it is possible to prepare pharmaceutical formulations containing cortexolone-17α-propionate in concentrations greater than 2% by weight as a therapeutic agent for topical administration. These pharmaceutical formulations have advantageous properties for the treatment of alopecia and provide optimal topical delivery of the therapeutic agent as evidenced by the pharmacokinetic profile described herein. In particular, this pharmacokinetic profile allows the formulations described herein to advantageously maximize topical delivery of cortexolone-17α-propionate to the skin and/or scalp, while simultaneously Shows minimal systemic exposure to any of the metabolites. As a result of such drug deposition, favorable clinical outcomes may be realized after daily topical administration for an appropriate period of time, such as days, weeks, or months. Moreover, it has also been discovered that the pharmaceutical formulations described herein have an advantageous stability profile, allowing storage of the finished product at room temperature for at least two years.

In certain embodiments, the present invention provides a method of treating alopecia in a patient in need thereof, comprising administering to the patient at least 2.1% by weight of cortexolone-17α-propionate and one or more pharmaceutical agents. and topically administering a pharmaceutical formulation containing an acceptable solvent.

In certain embodiments, the pharmaceutical formulation comprises from about 2.1% to about 20% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises from about 2.1% to about 17% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises from about 2.5% to about 17% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical composition comprises about 2.5% to 15% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical composition comprises from about 3% to about 15% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 6% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 7% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 7.5% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 8% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 9% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 10% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 11% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 12% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 13% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 14% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 15% by weight cortexolone-17α-propionate.

In certain embodiments, the pharmaceutical formulation comprises about 2.1% to about 5.5% by weight cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 2.5% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 3% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 4% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 5% by weight of cortexolone-17α-propionate. In yet a further embodiment, the pharmaceutical formulation comprises about 5.5% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises 5% by weight of cortexolone-17α-propionate.

In certain embodiments, the pharmaceutical formulation is a liquid or semi-solid formulation. In a further embodiment, the pharmaceutical formulation is a solution, suspension, emulsion, microemulsion, cream, gel, foam, or ointment.

In certain embodiments, the pharmaceutical formulation is anhydrous and contains less than about 5% water by weight. In a further embodiment, the pharmaceutical formulation is a solution.

In certain embodiments, the formulation provides an average C _max of cortexolone-17α-propionate of about 0.5 to about 3 ng/ml after topical application of a single dose. In certain embodiments, the average C _max of cortexolone-17α-propionate after administration of a single topical dose is from about 0.5 to about 1.5 ng/ml. In another embodiment, the mean C _max of cortexolone-17α-propionate after administration of a single topical dose is 1.04 ± 0.41 ng/ml.

In another embodiment, the formulation has a mean C _max of cortexolone-17α-propionate of less than about 3 ng/ml after topical application of a single dose comprising about 50 mg of cortexolone-17α-propionate. provides.

In some embodiments, the formulation provides a mean T _max of cortexolone-17α-propionate of less than about 20 hours following administration of a single topical dose. In another embodiment, the formulation provides a mean T _max of cortexolone-17α-propionate of less than about 15 hours following administration of a single topical dose. In another embodiment, the formulation provides a mean T _max of cortexolone-17α-propionate of less than about 12 hours following administration of a single topical dose. And, in another embodiment, the formulation has a mean T of cortexolone-17α-propionate of about 6.22 ± 5.17 hours following topical administration of a single dose comprising about 50 mg of cortexolone-17α-propionate. _max is provided.

In certain embodiments, the formulation provides a mean AUC _0-t of less than about 25 (ng*h)/ml following topical administration of a single dose comprising about 50 mg of cortexolone-17α-propionate. In another embodiment, the formulation provides a mean AUC _0-t of less than about 20 (ng*h)/ml after topical administration of a single dose comprising about 50 mg of cortexolone-17α-propionate. And, in another embodiment, the formulation provides a mean AUC _0-t of about 15.69 ± 4.3 (ng*h)/ml after topical administration of a single dose comprising about 50 mg of cortexolone-17α-propionate. do.

In some embodiments, the formulation has a mean stability of cortexolone-17α-propionate of about 3.82 ± 1.34 ng/ml following topical administration of a single dose comprising about 50 mg of cortexolone-17α-propionate. Provides steady-state C _max .

In some embodiments, the formulation has a mean steady-state T of cortexolone-17α-propionate of about 4.38 ± 1.96 hours following topical administration of a single dose comprising about 50 mg of cortexolone-17α-propionate. _max is provided.

In some embodiments, the formulation has a mean steady-state AUC _0-t of about 37.37 ± 12.36 (ng*h)/ml after topical administration of a single dose comprising about 50 mg of cortexolone-17α-propionate. to provide.

In some embodiments, formulations of the invention provide a mean change from baseline in target area hair count of at least 8 hairs/cm 2 after 6 months of daily application or BID application.

In some embodiments, the alopecia is androgenetic alopecia, alopecia areata, telogen effluvium, anagen efffluvium, traction alopecia, or any combination thereof. In certain embodiments, alopecia areata includes diffuse alopecia areata, alopecia areata monolocularis, alopecia areata multilocularis, ophiasis, alopecia totalis, and alopecia totalis. It is selected from the group consisting of alopecia universalis.

In some embodiments, the alopecia is androgenetic alopecia.

In some embodiments, the formulation further comprises at least one antioxidant, at least one emulsifier, or a combination thereof.

In some embodiments, the formulation is administered once or twice daily.

In some embodiments, the dosage form is liquid.

In some embodiments, about 0.2 to about 2.0 ml of formulation is administered during each application.

In a further embodiment, the invention provides a topical pharmaceutical formulation comprising cortexolone-17α-propionate at a concentration of at least 2.1% by weight and one or more pharmaceutically acceptable solvents.

In certain embodiments, the formulation comprises from about 2.1% to about 20% by weight cortexolone-17α-propionate. In another embodiment, the formulation comprises from about 2.1% to about 17% by weight cortexolone-17α-propionate. In another embodiment, the formulation comprises from about 2.5% to about 17% by weight cortexolone-17α-propionate. In another embodiment, the composition comprises about 2.5% to 15% by weight cortexolone-17α-propionate. In another embodiment, the composition comprises from about 3% to about 15% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 6% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 7% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 7.5% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 8% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 9% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 10% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 11% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 12% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 13% by weight cortexolone-17α-propionate. In another embodiment, the formulation includes about 14% by weight cortexolone-17α-propionate. In another embodiment, the formulation comprises about 15% by weight cortexolone-17α-propionate.

In certain embodiments, the formulation includes cortexolone-17α-propionate at a concentration of about 2.1% to about 5.5% by weight. In another embodiment, the formulation includes about 2.5% by weight cortexolone-17α-propionate. In another embodiment, the topical pharmaceutical formulation comprises about 3% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 4% by weight of cortexolone-17α-propionate. In another embodiment, the pharmaceutical formulation comprises about 5% by weight of cortexolone-17α-propionate. In yet a further embodiment, the pharmaceutical formulation comprises about 5.5% by weight of cortexolone-17α-propionate. And, in another embodiment, the pharmaceutical formulation includes 5% by weight of cortexolone-17α-propionate.

In certain embodiments, the pharmaceutical formulation is a liquid or semi-solid formulation. In some embodiments, the liquid or semi-solid dosage form is a solution, suspension, emulsion, microemulsion, cream, gel, foam, or ointment.

In some embodiments, the pharmaceutical formulation is anhydrous and contains less than about 5% water by weight. In another embodiment, the pharmaceutical formulation is anhydrous and contains less than about 3% water by weight.

In some embodiments, the topical pharmaceutical formulation is a solution.

In some embodiments, the formulation has an average stability of less than about 7.0 ng/ml of cortexolone-17α-propionate upon application of an amount of the formulation comprising about 50 mg of cortexolone-17α-propionate. Provides state C _max .

In another embodiment, the formulation has an average steady-state T of cortexolone-17α-propionate of less than about 8.0 hours upon application of an amount of the formulation comprising about 50 mg of cortexolone-17α-propionate. _max is provided.

In certain embodiments, the formulation contains less than about 64.1 (ng*h)/ml of cortexolone-17α-propionate upon application of an amount of the formulation comprising about 50 mg of cortexolone-17α-propionate. Provides the AUC _τ of .

In certain embodiments, the formulation is for use in the treatment of alopecia.

In certain embodiments, the one or more pharmaceutically acceptable solvents are selected from the group consisting of polyols, polyol ethers, and C ₁ -C ₇ alcohols. In some embodiments, the C ₁ -C ₇ alcohol is ethanol, isopropanol, or methanol. In another embodiment, the C ₁ -C ₇ alcohol is ethanol. In certain embodiments, the ethanol is 96°. In some embodiments, the ethanol is absolute ethanol.

In some embodiments, the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerol, and hexanetriol. In certain embodiments, the polyol is propylene glycol.

In certain embodiments, the polyol ether is selected from the group consisting of polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, and diethylene glycol monoethyl ether. In certain embodiments, the polyol ether is diethylene glycol monoethyl ether.

In some embodiments, the polyol is propylene glycol, the polyol ether is diethylene glycol monoethyl ether, and the C ₁ -C ₇ alcohol is ethanol.

In certain embodiments, the formulation is anhydrous and contains less than 5% water by weight or less than 3% water by weight.

In another embodiment, the formulation further includes an emulsifier.

In certain embodiments, the formulation further includes an antioxidant. In some embodiments, the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol, and propyl gallate. In certain embodiments, the antioxidant is ascorbyl palmitate.

In certain embodiments, the emulsifier is PEG-15 hydroxystearate (also known as polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, polysorbate. 20, polysorbate 60, polysorbate 80, PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, propylene glycol esters of fatty acids, polyglycerol esters of fatty acids, polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, caprylocapryl polyoxyl-8 glyceride; It is selected from the group consisting of caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, oleoyl polyoxylglyceride, and any combinations thereof. In certain embodiments, the emulsifier is polysorbate 80.

In another embodiment, the present invention provides a method of treating alopecia, comprising topically administering to a subject in need of treatment a topical pharmaceutical formulation described herein for at least 6 months. Twice daily topical administration of the formulation achieves hair growth comparable to that observed upon administration of oral finasteride for the same period of time. In one aspect, the method provides a reduced incidence of adverse effects selected from the group consisting of reduced sexual desire, erectile dysfunction (erectile dysfunction), ejaculatory dysfunction, and reduced ejaculate volume.

In another embodiment, the present invention provides a method of treating alopecia, comprising topically administering to a subject in need of treatment a topical pharmaceutical formulation described herein for at least 6 months. Topical administration of the formulation achieves a mean change from baseline in non-downy target area hair count (TAHC) of about 12.7 compared to vehicle.

In another embodiment, the present invention provides a method of treating alopecia, comprising topically administering to a subject in need of treatment a topical pharmaceutical formulation described herein for at least 6 months. Topical administration of the formulation achieves a weighted average Hair Growth Assessment (HGA) score of approximately 0.30 compared to vehicle.

In another embodiment, the present invention provides a method of treating alopecia, comprising topically administering to a subject in need of treatment a topical pharmaceutical formulation described herein for at least 6 months. Topical administration of the formulation achieves a weighted average Investigator's Global Assessment (IGA) score of approximately 0.43 compared to vehicle.

In another embodiment, the present invention provides a method of treating alopecia, comprising topically administering to a subject in need of treatment a topical pharmaceutical formulation described herein for at least 6 months. Topical administration of the formulation has no systemic antiandrogenic side effects.

In another embodiment, the present invention provides a method of treating alopecia, comprising topically administering to a subject in need of treatment alopecia a topical pharmaceutical formulation described herein, wherein topical administration of the formulation comprises: Provides:

Mean change from baseline in target area hair count of 9 hairs/cm 2 or more after 6 months of daily or BID application; or

Mean change from baseline in target area hair count of 10 hairs/cm 2 or more after 6 months of daily application or BID application; or

Mean change from baseline in target area hair count of 11 hairs/cm 2 or more after 6 months of daily or BID application; or

Mean change from baseline in target area hair count of 12 hairs/cm 2 or more after 6 months of daily or BID application; or

Weighted average HGA score of 0.20 or greater after 6 months of daily application or BID application; or

Weighted average HGA score of 0.30 or greater after 6 months of daily application or BID application; or

Weighted average HGA score of 0.40 or greater after 6 months of daily application or BID application; or

Weighted average IGA score of 0.10 or greater after 6 months of daily application or BID application; or

Weighted average IGA score of 0.20 or greater after 6 months of daily application or BID application; or

Weighted average IGA score of 0.30 or greater after 6 months of daily application or BID application; or

Good (positive) HGA scores in at least about 10% of subjects after 6 months of daily application or BID application; or

Good (positive) HGA scores in at least about 20% of subjects after 6 months of daily application or BID application; or

Good (positive) HGA scores in at least about 30% of subjects after 6 months of daily application or BID application; or

Good (positive) IGA scores in at least about 10% of subjects after 6 months of daily application or BID application; or

Good (positive) IGA scores in at least about 20% of subjects after 6 months of daily application or BID application; or

Good (positive) IGA scores in at least about 30% of subjects after 6 months of daily application or BID application; or

Good (positive) IGA scores in at least about 40% of subjects after 6 months of daily application or BID application.

The foregoing summary as well as the detailed description of the embodiments below will be better understood when read in conjunction with the accompanying drawings. For illustrative purposes, the drawings may depict the use of specific embodiments. However, it should be understood that the compounds, formulations and compositions described herein are not limited to the precise embodiments discussed or depicted in the figures.
Figure 1 shows the frequency distribution of hair growth assessments (HGA) performed by study subjects in the two treatment groups after 6 months of treatment in the Phase 2 clinical study in men with androgenetic alopecia (AGA) described in Example 9. indicates.
Figure 2 shows the frequency distribution of Investigator Global Assessment (IGA) for hair growth in the two treatment groups after 6 months of treatment in the Phase 2 clinical study in men with AGA described in Example 9.

The formulations described herein constitute a major improvement over the currently available therapies for alopecia, specifically AGA, and will enable practitioners to have an effective, useful and safe treatment for alopecia, especially AGA.

The pharmaceutical formulations for topical administration described herein provide optimal topical delivery of the therapeutic agent cortexolone-17α-propionate and, when used in the treatment of alopecia, particularly AGA, in terms of efficacy, with minimal side effects. , it was confirmed that similar results could be achieved with commercially available finasteride 1 mg tablets (PROPECIA®) administered orally once daily. PROPECIA® is approved for the treatment of AGA. Example 11 Comparison of the effectiveness of the formulations described herein with the effectiveness of PROPECIA®, based on information provided in the PROPECIA® package insert and available on the US Food and Drug Administration website is provided in.

The pharmaceutical formulations described herein minimize systemic exposure and are therefore safe. The results of the study described in Example 9 of the Experimental section demonstrate that the 5% solution of cortexolone-17α-propionate was well tolerated topically. The incidence of local intolerance signs was low, and the incidence of “treatment-induced” local intolerance signs was generally similar between the Cortexolone-17α-propionate solution 5% treatment group and the vehicle treatment group. Most local signs of intolerance were minimal/mild to mild in severity. Exfoliation and pruritus were the most frequently observed “treatment-induced” signs, with fewer subjects having erythema, folliculitis, and hyperpigmentation. Additionally, the incidence of adverse events (AEs) was similar between the two treatment groups, with most events typically mild in severity and not related to the test subject. Importantly, no AEs that could be correlated with the systemic antiandrogenic activity of cortexolone-17α-propionate (e.g., decreased libido, erectile dysfunction, and ejaculatory dysfunction) occurred during the 6-month treatment. The study of Example 9 also demonstrated that the formulations described herein, when applied topically on the scalp, achieve localized delivery of the therapeutic agent while avoiding excessive systemic distribution thereof, which can lead to the development of anti-androgenic effects in treated subjects. It confirms that it is optimal for doing so. After application of cortexolone-17α-propionate on the scalp, low levels of circulating cortexolone-17α-propionate are also evident from the PK parameters illustrated in Example 6. At least these properties differentiate the formulation described herein from finasteride 1 mg tablets (PROPECIA®), which, as recorded in the PROPECIA® appendix, is associated with reduced sexual desire, erectile dysfunction (erectile dysfunction), ejaculatory dysfunction, and reduced ejaculate volume. These adverse events with PROPECIA®, reported in more than 1% of patients, are caused by the systemic antiandrogenic activity exerted by the treatment. Unlike PROPECIA®, the formulations described herein can maximize delivery of the therapeutic agent to the target site (i.e., hair follicles) while minimizing its systemic absorption, resulting in significant adverse events, including those due to systemic antiandrogenic effects. In the absence of , this translates into a pharmacological profile characterized by efficacy in promoting hair regrowth (due to local activity on hair follicles).

Based on the studies described in the experimental section, it is clear that the formulations described herein represent a significant improvement over the currently available systemic antiandrogenic drug, PROPECIA®, for the treatment of AGA. An exemplary formulation of the invention disclosed in Example 4b, when tested in a phase II clinical trial in subjects affected by AGA (with topical application twice daily on the scalp in the affected area for 6 months), produced two co- Demonstrated to be effective in stimulating hair growth, as assessed by the primary endpoint (mean change from baseline in TAHC of non-down hair and subject self-assessment HGA questionnaire), vehicle There was a larger improvement compared to . As discussed in Example 11, topical administration of this exemplary formulation of Example 4b resulted in a mean change in TAHC of non-down hair at 6 months, reduced sexual desire, erectile dysfunction (erectile dysfunction), and ejaculatory dysfunction. Almost identical to that of PROPECIA® at 6 months, without the systemic antiandrogenic effects known to be responsible for the major side effects of PROPECIA® (calculated from published results of two Phase III clinical studies of Propecia®) was 12.2, compared to 12.7 for the formulation of Example 4b.

Articles (“a”, “an”, and “the”) are used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, “element” means one element or more than one element.

As used herein, the term “about” means ±10% of the stated value, unless otherwise indicated.

As used herein, the phrases “active agent” and “therapeutic agent” are interchangeable and refer to cortexolone-17α-propionate.

As used herein, the term “alopecia” refers to alopecia areata, collectively or individually as specified, including alopecia areata (androgenetic alopecia (AGA)), alopecia areata (alopecia areata diffuse, alopecia areata monofocal, alopecia areata multiplex, alopecia areata, frontal alopecia), androgenetic alopecia (AGA). alopecia, and alopecia universalis), telogen effluvium, anagen alopecia, and traction alopecia.

As used herein, the term “anhydrous” means substantially free of water, i.e., less than about 5% by weight water, and in certain embodiments as specified herein, less than about 3% by weight water. It means having.

As used herein, the term “antioxidant” includes pharmaceutically acceptable antioxidants known to those skilled in the art. Examples include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol (also known as vitamin E), and propyl gallate. .

As used herein, the phrase “area under the curve” or “AUC” refers to the amount of the active agent over time following application of a dose of the active agent (or, as specified, one of its metabolites) itself or a formulation containing it. It refers to the area under the curve defined by the change in plasma concentration. “AUC _0-∞ ” is the area under the concentration-time curve extrapolated from t ₀ to infinity after application of the dose. “AUC _0-t ” is the area under the concentration-time curve from time 0 to time t after application of the dose, where t is the last time point with a measurable concentration. AUC _τ is referred to as meaning steady-state AUC.

As used herein, the phrase “C ₁ -C ₇ alcohol” refers to alcohols having up to 7 carbons suitable for use in topical pharmaceutical formulations. Examples of such C ₁ -C ₇ alcohols include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, benzyl alcohol, etc. Without wishing to be bound by any particular theory, C ₁ -C ₇ alcohols, especially short chain C ₁ -C ₇ alcohols such as ethyl, propyl or isopropyl alcohol, have solubilizing activity towards cortexolone-17α-propionate. It is believed to be effective. Such C ₁ -C ₇ alcohols are further believed to contribute to the spreadability of the formulations described herein.

As used herein, the term “C _max ” refers to the maximum concentration of an active agent or its metabolite on a graph of plasma concentration of the active agent (or its metabolite) versus time. C _maxτ refers to the maximum concentration of the active agent or its degradation product on a graph of the plasma concentration of the active agent (or its degradation product or metabolite) versus time when the steady-state level is reached.

As used herein, “cortexolone” (also known as “11-deoxycortisol” or “Reichstein's substance”) refers to a compound having the structure:

As used herein, “cortexolone-17α-propionate” refers to the compound 17α-propionyloxy-21-hydroxy-pregna-4-en-3,20-dione, which Equivalent to the following chemical structure:

As used herein, the term “metabolite” refers to a compound resulting from the in vivo metabolism or breakdown of cortexolone-17α-propionate. Exemplary known metabolites include, but are not limited to, cortexolone and tetrahydrocortexolone.

As used herein, the term “degradation product” refers to a compound resulting from the in vitro degradation of cortexolone-17α-propionate. Exemplary known cortexolone-17α-propionate breakdown products include, but are not limited to, cortexolone-21-propionate and cortexolone.

As used herein, the term “ester” refers to an esterifying organic solvent, including but not limited to ethyl acetate and ethyl lactate.

As used herein, the phrase “natural oil” refers to an oil that can be isolated from natural sources. Exemplary natural oils include, but are not limited to, almond oil, olive oil, cottonseed oil, safflower oil, etc.

As used herein, the term “polyol” refers to an organic molecule containing two or more hydroxyl groups. Exemplary polyols include, but are not limited to, ethylene glycol, propylene glycol, glycerol, hexanetriol, etc.

As used herein, the phrase “polyol ether” refers to a polyol ether suitable for use in topical pharmaceutical formulations. Exemplary polyol ethers include, but are not limited to, polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether, and the like.

As used herein, the phrase “penetration enhancer” refers to a pharmaceutically acceptable compound that increases penetration of an active agent. Exemplary penetration enhancers include polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether (TRANSCUTOL®), dimethyl isosor. Vide, diethyl sebacate, azone, menthol, nerol, camphor, methyl salicylate, Tween 80, SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (CREMOPHOR® RH40, KOLLIPHOR® RH40), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB), fatty acid esters such as isopropyl myristate, isopropyl palmitate, etc., fatty acids such as oleic acid, palmitic acid, linoleic acid, and salts thereof, fatty alcohols such as Including, but not limited to, oleyl alcohol, myristyl alcohol, stearyl alcohol, etc., medium chain triglycerides, and combinations of any of these.

As used herein, the term “solvent” refers to a pharmaceutically acceptable solvent for topical application, including without limitation the scalp, used to solubilize cortexolone-17α-propionate in the formulations described herein. means an acceptable solvent or a mixture of more than one pharmaceutically acceptable solvent.

As used herein, “tetrahydrocortexolone” refers to the compound having Chemical Abstracts Service (CAS) registration number 68-60-0.

As used herein, the term “T _max ” refers to the time point after application of an active agent (or its metabolite) at which the maximum plasma concentration of the active agent is reached. The term T _max refers to the time at which the active agent or its metabolite is at its maximum concentration on a graph of the plasma concentration of the active agent (or its metabolite) against the time when the steady-state level is reached.

The terms “treat,” “treating,” and “treatment” refer to any indication of success in treating or ameliorating an injury, disease, or condition, including reduction of symptoms; remission; such as reducing or making an injury, disease, or condition more tolerable to the patient; slowing the rate of degeneration or degradation; or any objective or subjective parameter that improves the patient's physical or mental well-being. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric testing, or psychiatric evaluation.

The term "preventing" means preventing the occurrence, presence, or alternatively delaying the onset or recurrence of the disease, disorder, or condition to which the term applies, or of one or more symptoms associated with the disease, disorder, or condition. refers to something The term “preventing” also refers to reducing the incidence of a disease, disorder or condition. The term “prevention” refers to a preventive action.

As used herein, the phrase "weight percent" refers to the practice in which weight percent is weight percent by volume (w/v) and percent weight by total weight (w/w) for a given value. It is intended to include and disclose forms. By way of example, an embodiment comprising 10% by weight of the element “X” discloses an embodiment comprising both 10% by weight “X” (w/v) and 10% by weight “X” (w/w) . Similarly, and also by way of example, embodiments comprising 10% by weight "X", 20% by weight "Y", and 60% by weight "Z" disclose embodiments comprising: a) 10% by weight “X” (w/v), 20% by weight “Y” (w/v), and 60% by weight “Z” (w/v); and b) 10% by weight “X” (w/w), 20% by weight “Y” (w/w), and 60% by weight “Z” (w/w). Notwithstanding the above, in certain embodiments, the values will specifically be expressed as “(w/w)” or “(w/v).” In such cases, the values should be construed as disclosing only the values indicated, i.e., only (w/w) or only (w/v) and not both.

As used herein, the terms “comprise,” “including,” “having,” “comprising,” “containing,” etc. are open meaning “including but not limited to.” -ended) term. To the extent that a given embodiment disclosed herein “includes” certain elements, the invention also includes embodiments “consisting essentially of” such elements and embodiments “consisting of” such elements. It should be understood that it specifically considers and discloses.

As used herein, the terms “consisting essentially of,” “consisting essentially of,” etc. should be construed as semi-closed terms, which substantially affect the basic and novel characteristics of the embodiments. This means that no other ingredients are included.

As used herein, the terms “consisting of,” “consisting of,” etc. are to be construed as closed terms, such that an embodiment “consisting of” a particular set of elements is not specified in that embodiment. Any element, step or ingredient must be excluded.

As used herein, the term “Target Area Hair Count” or “TAHC” refers to the change from baseline in the number of non-fuzz hairs in a target area of the scalp. The target area may be, for example, a 1 cm 2 or 1 inch diameter circle (5.1 cm 2 ).

As used herein, the term "Hair Growth Assessment" or "HGA" refers to comparing a baseline standardized global photo of a subject's scalp to a "real-time" standardized global photo. refers to the score provided by

As used herein, the term "Investigator's Global Assessment" or "IGA" refers to a score provided by an evaluator by comparing a baseline standardized global photograph of a subject's scalp to a "real-time" standardized global photograph. refers to

As used herein, the term “Bis In Die” or “BID” means “twice a day.”

As used herein, the term “allocation group” refers to a group of people participating in a clinical trial who are randomly assigned to a group receiving the treatment under study or to a group receiving standard treatment (or placebo treatment) as a control group. refers to a group.

As used herein, the term "ethanol" means ethyl alcohol, CH ₃ CH ₂ OH, and includes pure (absolute) ethanol and 96° ethanol, the latter typically in the range of about 4% by volume to about It is ethanol containing water in an amount in the range of 5.1% by volume.

The present invention provides a cortexolone-17α-propionate comprising a solvent and at least 2.1% by weight of cortexolone-17α-propionate up to about 20% by weight of cortexolone-17α-propionate, including all intermediate values therebetween. A fully solubilized pharmaceutical formulation of Texolone-17α-propionate is provided. In certain embodiments, the formulation comprises at least 2.1% by weight and up to about 17% cortexolone-17α-propionate, at least 2.5% by weight and up to about 17% cortexolone-17α-propionate, at least 2.5% by weight up to about 15% cortexolone-17α-propionate, or at least 3% by weight up to about 15% cortexolone-17α-propionate. In other embodiments, the formulation comprises about 6, about 7, about 7.5, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15 weight percent cortexolone-17α-pro. May contain cypionate.

The invention also provides a solvent comprising at least 2.1% by weight of cortexolone-17α-propionate and up to about 5.5% by weight of cortexolone-17α-propionate, including all intermediate values therebetween. A fully solubilized pharmaceutical formulation of cortexolone-17α-propionate is provided. In certain embodiments, the formulation comprises at least 2.2 to up to about 5.5 weight percent cortexolone-17α-propionate, at least 2.3 to up to about 5.5 weight percent cortexolone-17α-propionate, at least 2.4 to up to about 5.5% by weight cortexolone-17α-propionate, at least 2.5 to up to about 5.5% by weight cortexolone-17α-propionate, at least 2.6 to up to about 5.5% by weight cortexolone-17α-propionate. , at least 2.7 to up to about 5.5% by weight of cortexolone-17α-propionate, at least 2.8 to up to about 5.5% by weight of cortexolone-17α-propionate, at least 2.9 to up to about 5.5% by weight of Cortex. solon-17α-propionate, or at least 3.0% and up to about 5.5% by weight cortexolone-17α-propionate. In other embodiments, the formulation may include about 2.3, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, or about 5.5 weight percent cortexolone-17α-propionate. In certain embodiments, the formulation may include about 5% by weight of cortexolone-17α-propionate. In each of these embodiments, cortexolone-17α-propionate is fully solubilized in the formulation. As used herein, “fully solubilized” means that at least 95%, at least 98%, at least 99%, or at least 99.9% by weight of cortexolone-17α-propionate is solubilized in the formulation. do.

Cortexolone-17α-propionate solubility exceeding 2% by weight has not been previously reported and has been difficult to achieve. For example, International Patent Application Publication No. WO 2009/019138 discloses formulations with up to 2% by weight of cortexolone-17α-propionate, but does not specify whether or how formulations with higher concentrations could be prepared. It does not teach or imply that a formulation will be prepared.

Similarly, Celasco, et al., Arzneim.-Forsch./Drug Res. 54, no. 12, 881-886 (2004) teaches suspending a 5 mg sample of cortexolone-17α-propionate in 0.2 ml of suspension vehicle. However, as with International Patent Application Publication No. WO 2009/019138, Celasco does not state whether fully solubilized high concentration formulations can or will be prepared.

In certain embodiments, the formulation is anhydrous and contains less than about 5% water by weight. In a further embodiment, the anhydrous formulation includes less than about 3% water by weight.

In certain embodiments, the formulation may be liquid (including, for example, a solution or suspension or emulsion or microemulsion) or semisolid (including, for example, a cream, gel, or ointment, or foam). there is. Regardless of the form of the formulation (solution, gel, emulsion, etc.), the formulation has a consistency suitable for spreading on the scalp and/or skin.

In one embodiment, the formulation may be a liquid formulation.

In other embodiments, the formulation may be anhydrous. In other embodiments, the formulation may be a solution. In some embodiments, the solution is anhydrous and has less than about 5% water by weight. In other embodiments, the anhydrous solution has less than about 3% water by weight.

In one embodiment, the invention provides a pharmaceutical formulation suitable for topical administration, said formulation comprising cortexolone-17α-propionate in an amount of at least 2.1% by weight and one or more pharmaceutically acceptable solvents. .

In another embodiment, the present invention provides a pharmaceutical formulation suitable for topical administration, said formulation comprising cortexolone-17α-propionate in an amount ranging from about 2.1% by weight to about 20% by weight and one or more pharmaceutical agents. Contains acceptable solvents. Suitable ranges and amounts of cortexolone-17α-propionate in this aspect of the invention are described above with respect to topical pharmaceutical formulations comprising cortexolone-17α-propionate.

In another embodiment, the present invention provides a pharmaceutical formulation suitable for topical administration, said formulation comprising cortexolone-17α-propionate in an amount ranging from about 2.1% by weight to about 5.5% by weight and one or more pharmaceutical agents. Contains acceptable solvents. Suitable ranges and amounts of cortexolone-17α-propionate in this aspect of the invention are described above with respect to topical pharmaceutical formulations comprising cortexolone-17α-propionate.

In another embodiment, the present invention provides a pharmaceutical formulation suitable for topical administration for use in the treatment and/or prevention of alopecia, said formulation comprising cortexolone-17α-propionate in an amount of at least 2.1% by weight. and one or more pharmaceutically acceptable solvents.

In another embodiment, the present invention provides a pharmaceutical formulation suitable for topical administration for use in the treatment and/or prevention of alopecia, said formulation comprising cortexolone- in an amount ranging from about 2.1% to about 20% by weight. 17α-propionate and one or more pharmaceutically acceptable solvents. Suitable ranges and amounts of cortexolone-17α-propionate in this aspect of the invention are described above with respect to topical pharmaceutical formulations comprising cortexolone-17α-propionate.

In another embodiment, the present invention provides a pharmaceutical formulation suitable for topical administration for use in the treatment and/or prevention of alopecia, said formulation comprising cortexolone in an amount ranging from about 2.1% to about 5.5% by weight. -17α-propionate and one or more pharmaceutically acceptable solvents. Suitable ranges and amounts of cortexolone-17α-propionate in this aspect of the invention are described above with respect to topical pharmaceutical formulations comprising cortexolone-17α-propionate.

In another embodiment, the present invention provides a method for treating and/or preventing alopecia in a mammal in need thereof, comprising administering to the topical an effective amount of a pharmaceutical formulation suitable for topical administration. and administering, wherein the formulation comprises cortexolone-17α-propionate in an amount of at least 2.1% by weight and one or more pharmaceutically acceptable solvents.

A further aspect of the invention is a method for treating and/or preventing alopecia in a mammal in need thereof, said method comprising topical administration of a therapeutic amount of a pharmaceutical formulation suitable for topical administration. The formulation includes cortexolone-17α-propionate and one or more pharmaceutically acceptable solvents in an amount ranging from about 2.1% by weight to about 20% by weight. Suitable ranges and amounts of cortexolone-17α-propionate in this aspect of the invention are described above with respect to topical pharmaceutical formulations comprising cortexolone-17α-propionate.

A further aspect of the invention is a method for treating and/or preventing alopecia in a mammal in need thereof, said method comprising topical administration of a therapeutic amount of a pharmaceutical formulation suitable for topical administration. and the formulation includes cortexolone-17α-propionate in an amount ranging from about 2.1% by weight to about 5.5% by weight and one or more physiologically acceptable solvents. Suitable ranges and amounts of cortexolone-17α-propionate in this aspect of the invention are described above with respect to topical pharmaceutical formulations comprising cortexolone-17α-propionate.

In certain embodiments, the mammal is a human.

In certain embodiments, topical administration includes application of the formulation to the skin and/or scalp.

In certain embodiments, the alopecia is alopecia areata androgenetic alopecia (AGA), alopecia areata (including alopecia areata diffuse, alopecia areata monofocal, alopecia areata multifocal, alopecia areata, alopecia totalis, and alopecia universalis), telogen effluvium, alopecia areata, and It is traction alopecia. In certain embodiments, the alopecia is AGA.

In certain embodiments, the pharmaceutical formulation may be in the form of a solution, gel, flowable ointment, suspension, microemulsion, or foam.

In addition to the solvent and the specified amount of cortexolone-17α-propionate, the formulations described herein may also optionally contain at least one penetration enhancer, and optionally at least one pharmaceutically acceptable excipient.

In certain embodiments, the formulation may further include at least one antioxidant, at least one emulsifier, or a combination thereof.

menstruum

In certain embodiments, the solvent is anhydrous and may include less than about 5% water by weight. In other embodiments, the solvent is anhydrous and may contain less than about 3% water by weight.

In certain embodiments, the solvent is water, C ₁ -C ₇ alcohol, polyol ether, polyol, natural oil, ester, tricapryline (2,3-di(octanoyloxy)propyl octanoate), medium chain triglyceride. glyceride, caprylocaproyl polyoxyl-8 glyceride, and any combination thereof.

In some embodiments, the formulation may include at least about 50% by weight solvent. In other embodiments, the formulation may include at least about 60% by weight solvent. In other embodiments, the formulation may include at least about 70% by weight solvent. In other embodiments, the formulation may include at least about 80% by weight solvent. In other embodiments, the formulation comprises at least about 85% solvent by weight, at least about 90% solvent by weight, at least about 91% solvent by weight, at least about 92% solvent by weight; at least about 93% by weight solvent; at least about 94% by weight solvent; or at least about 95% by weight of solvent.

In certain embodiments, the solvent may include a mixture of C ₁ -C ₇ alcohols, polyol ethers, polyols. In such embodiments, the formulation contains from about 10 to about 50 weight percent polyol ether; About 5% to about 55% by weight polyol; and about 5 to about 50 weight percent C ₁ -C ₇ alcohol. In certain embodiments, the mixture of C ₁ -C ₇ alcohols, polyol ethers, and polyols may be present in about a 1:1:1 ratio on a w/w/w basis. In certain embodiments, the C ₁ -C ₇ alcohol, polyol ether, and polyol are each present at about 30 weight percent.

In certain embodiments, the formulation contains from about 15 to about 45 weight percent polyol ether; About 20 to about 40 weight percent polyol ether; About 25 to about 35 weight percent polyol ether; or about 30 to about 35 weight percent polyol ether. In certain embodiments, the formulation may include about 30% polyol ether by weight. In another embodiment, the formulation may include about 32% polyol ether by weight.

In certain embodiments, the polyol ether is of or from the group comprising polyethylene glycol, polypropylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, diethylene glycol monoethyl ether (TRANSCUTOL®), and combinations thereof. is selected from the group consisting of

When the polyol ether is polyethylene glycol, it may be selected from the group comprising or consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 540, and polyethylene glycol 600. In certain embodiments, the polyol ether can be polyethylene glycol 200. In another embodiment, the polyol ether can be polyethylene glycol 400. In another embodiment, the polyol ether can be diethylene glycol monoethyl ether.

In certain embodiments, the polyol may be selected from the group comprising or consisting of propylene glycol, ethylene glycol, glycerol, hexanetriol, and combinations thereof. In certain embodiments, the polyol can be glycerol. In another embodiment, the polyol can be propylene glycol.

In certain embodiments, the polyol comprises from about 5% to about 55% by weight of the total formulation; About 10% to about 50% by weight of the total formulation; About 20% to about 45% by weight of the total formulation; And in certain embodiments, it may be present in an amount ranging from about 25% to about 40% by weight. In certain embodiments, the polyol makes up about 30% by weight of the total formulation. In a further embodiment, the polyol comprising about 30% by weight of the total formulation may be propylene glycol.

In some embodiments, the formulation may include from about 5 to about 50 weight percent C ₁ -C ₇ alcohol. In certain embodiments, the formulation contains from about 15 to about 45 weight percent C ₁ -C ₇ alcohol; About 20 to about 40 weight percent C ₁ -C ₇ alcohol; or about 25 to about 35% by weight of C ₁ -C ₇ alcohol. In certain embodiments, the formulation may include about 30% by weight C ₁ -C ₇ alcohol. In yet a further embodiment, the formulation may include C ₁ -C ₇ alcohol in an amount ranging from about 10% to about 40% by weight, or from about 15% to about 35% by weight.

In certain embodiments, the C ₁ -C ₇ alcohol is selected from the group comprising or consisting of methanol, ethanol, isopropanol, n-butanol, n-propanol, and benzyl alcohol. In certain embodiments, the C ₁ -C ₇ alcohol is ethanol. In some embodiments, ethanol makes up about 30% by weight of the total formulation. In another embodiment, the C ₁ -C ₇ alcohol is isopropanol.

In some embodiments, the C ₁ -C ₇ alcohol may contain a small water fraction, generally ranging from about 4% by volume to about 5.1% by volume. In embodiments where the formulation is anhydrous, the C ₁ -C ₇ alcohol having about 4% to about 5.1% water by volume is added such that the water content in the finished formulation itself is less than about 5% or less than about 3% by weight. It may be present in the dosage form in an amount.

In certain embodiments, the solvent may include polyols, polyol ethers, and C ₁ -C ₇ alcohols. In certain embodiments, the solvent may include ethanol as the C ₁ -C ₇ alcohol, diethylene glycol monomethyl ether as the polyol ether, and propylene glycol as the polyol. These solvents may be present in any acceptable ratio, but typically are each present in about 25 to about 35 weight percent of the formulation.

penetration enhancer

In certain embodiments, in addition to solvents, formulations disclosed herein may include one or more penetration enhancers. Without wishing to be bound by a particular theory, it is believed that penetration enhancers have a beneficial effect on the delivery of therapeutic agents into the skin (including the scalp) and/or hair follicles. Advantageously and in some embodiments, the solvent or some component(s) of the solvent acts as a penetration enhancer. For example, in embodiments where the formulation includes ethanol and/or diethylene glycol monoethyl ether, these solvents may also act to enhance penetration of the active agent into the skin (including the scalp) and/or hair follicles. . Notwithstanding the presence of ethanol and/or diethylene glycol monoethyl ether, the formulations described herein may optionally further comprise additional penetration enhancers.

Examples of additional penetration enhancers that can be incorporated into the formulations described herein include polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol. Monoethyl ether (TRANSCUTOL®), dimethyl isosorbide, diethyl sebacate, azone, menthol, nerol, camphor, methyl salicylate, Tween 80, SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (CREMOPHOR® RH40, KOLLIPHOR® RH40), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB), fatty acid esters such as isopropyl myristate, isopropyl palmitate, etc., fatty acids such as oleic acid, palmitic acid , linoleic acid, and salts thereof, fatty alcohols such as oleyl alcohol, myristyl alcohol, stearyl alcohol, etc., medium chain triglycerides, and combinations of any of these.

In one embodiment, the penetration enhancer is dimethyl isosorbide. In another embodiment, the penetration enhancer is a mixture comprising dimethyl isosorbide and diethylene glycol monoethyl ether. In another embodiment, the at least one penetration enhancer is dimethyl sulfoxide.

In certain embodiments, the penetration enhancer may be present in an amount ranging from about 1% to about 50% by weight relative to the total weight of the formulation. In another embodiment, the penetration enhancer is present in an amount of from about 2% to about 40% by weight relative to the total weight of the formulation; Alternatively, it may be present from about 5% to about 35% by weight relative to the total weight of the formulation. According to some embodiments, the skin penetration enhancer is present in about 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about 25% by weight relative to the total weight of the formulation. %, about 30%, about 35%, about 40%, about 45%, or about 50% by weight.

other ingredients

Because oxidation can result in degradation of the active agent, in some embodiments, the formulation may additionally include up to about 1% by weight of antioxidant. The antioxidant may be selected from the group comprising or consisting of BHT, BHA, ascorbyl palmitate, ascorbic acid, alpha tocopherol (also known as vitamin E), propyl gallate, and any combinations thereof.

In certain embodiments, the formulation may include up to about 0.5% antioxidant by weight, or may include up to about 0.5% antioxidant by weight. In certain embodiments, the antioxidant may be ascorbyl palmitate. In another embodiment, the antioxidant may be BHA. In another embodiment, the antioxidant can be BHT. In yet a further embodiment, the formulation may include about 0.5% by weight ascorbyl palmitate.

In some embodiments, the formulation may further include an emulsifier. Without wishing to be bound by any particular theory, it is believed that emulsifiers, when present, assist or promote dissolution of any solid materials, such as active agents, in the formulation. However, in other embodiments, an emulsifier may be present to facilitate the incorporation of two immiscible liquids into one another (e.g., an emulsion or microemulsion).

In other embodiments, and without wishing to be bound by any particular theory, emulsifiers can increase product spreadability. For example, and without wishing to be bound by any particular theory, it is believed that when the formulation is a liquid solution, the presence of a suitable amount of emulsifier reduces the surface tension between the formulation and the lipid environment of the superficial layers of the skin and/or scalp. It is believed that this makes the formulation easier to spread and aids penetration of the therapeutic agent into the skin (including the scalp) and/or hair follicles.

In certain embodiments, the emulsifier is polyethylene glycol (PEG)-fatty acid monoester, such as PEG-15 hydroxystearate (also known as polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 Lau. late, PEG-40 oleate, etc.; polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, polysorbate 60, polysorbate 80, etc.; polyoxyethylene alkyl ethers such as PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000, etc.; Sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, etc.; propylene glycol esters of fatty acids; polyglycerol esters of fatty acids; polyoxyethylene castor oil derivatives such as polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, etc.; Caprylocapryl polyoxyl-8 glyceride; polyoxylglycerides, such as caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, oleoyl polyoxylglyceride, etc.; and any combination thereof.

In certain embodiments, the formulation may include an emulsifier in an amount of up to about 0.5% by weight of the total formulation. In some embodiments, the emulsifier may be present in an amount ranging from 0.05 to 0.2 weight percent. In yet a further embodiment, the formulation may include an emulsifier in an amount up to about 0.1% by weight, or it may include an emulsifier in an amount of up to about 0.1% by weight. In certain embodiments, the emulsifier may be polyoxyl 40 hydrogenated castor oil. In another embodiment, the emulsifier may be polyoxyl-15-hydroxystearate. In certain embodiments, the emulsifier may be polysorbate 80. In yet a further embodiment, the emulsifier is present in the formulation at about 0.1% by weight.

Pharmacokinetic parameters

The formulations described herein provide an acceptable pharmacokinetic profile of both cortexolone-17α-propionate and/or its metabolites, and the formulations described herein provide excellent local delivery of therapeutic agents while minimizing systemic exposure. It was surprisingly revealed that it appears to provide. This is a beneficial result because, without wishing to be bound by any particular theory, the active agent is believed to be most effective when delivered directly to the hair follicles rather than through the systemic circulation. Accordingly, an advantage of the formulations of the present invention is that they can deliver the active agent with sufficient penetration to reach the hair follicles after topical application, but without so much penetration as to be widely systemically available.

For example, in certain embodiments, the formulations described herein have a concentration of about 2 ng/ml to about 6 ng/ml; about 2.5 ng/ml to about 5.5 ng/ml; or an average steady-state C _max of cortexolone-17α-propionate of about 3 ng/ml to about 5 ng/ml. In certain embodiments, the average steady-state C _max of cortexolone-17α-propionate may be about 4 ng/ml, or about 3.8 ng/ml. In other embodiments, the average steady-state C _max may be less than about 6 ng/ml, less than about 5 ng/ml, less than about 4 ng/ml, less than about 3 ng/ml, or less than about 2 ng/ml.

In certain embodiments, formulations described herein can be administered for a period of time ranging from about 2 to about 7 hours; about 2.5 to about 6.5 hours; about 3 to about 6 hours; about 3.5 to about 5 hours; or an average steady-state T _max of cortexolone-17α-propionate of about 4 to about 5 hours. In certain embodiments, the average steady-state T _max of cortexolone-17α-propionate may be about 4.5 or 4.4 hours. In certain embodiments, the average steady-state T _max of cortexolone-17α -propionate may be less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about 5 hours, or less than about 4 hours.

The present formulation may also have a concentration of about 20 (ng*h)/ml to about 55 (ng*h)/ml; about 25 (ng*h)/ml to about 50 (ng*h)/ml; about 25 (ng*h)/ml to about 45 (ng*h)/ml; or from about 30 (ng*h)/ml _to about 40 (ng*h)/ml. In certain embodiments, the average AUC _τ may be about 35 (ng*h)/ml or about 37 (ng*h)/ml. In other embodiments, the AUC _τ is less than about 55 (ng*h)/ml, less than about 45 (ng*h)/ml, less than about 40 (ng*h)/ml, or less than about 35 (ng*h)/ml. It may be less than ml.

This formulation also provides a desirable release profile for cortexolone-17α-propionate. For example, after initial topical application of the formulation, in certain embodiments, less than about 0.5% of the administered cortexolone-17α-propionate may be detectable in the patient's urine. In another embodiment, the urine of the patient is determined to contain less than about 0.4%, less than about 0.35%, less than about 0.3%, or less than about 0.25%, less than about 0.2%, or less than about 0.15% of cortexolone-17α-propionate. can be detected in In certain embodiments, cortexolone-17α-propionate cannot be detected in the urine of a given patient.

In certain embodiments, after steady state is achieved, less than about 700 μg of administered cortexolone-17α-propionate can be detected in the patient's urine. In another embodiment, less than about 650 μg, less than about 600 μg, less than about 500 μg, less than about 400 μg, less than about 300 μg, or less than about 250 μg of cortexolone-17α-propionate is determined in the urine of the patient. can be detected in In certain embodiments, even after steady state is achieved, cortexolone-17α-propionate cannot be detected in the urine of a given patient.

In certain embodiments, cortexolone can also be detected in the patient's urine. For example, in certain embodiments, less than about 0.5 μg of cortexolone can be detected in the patient's urine after initial topical application of the formulation. In other embodiments, less than about 0.4 μg, less than about 0.35 μg, less than about 0.3 μg, or less than about 0.25 μg, less than about 0.2 μg, or less than about 0.15 μg of cortexolone can be detected in the urine of a given patient. . In certain embodiments, cortexolone cannot be detected in the urine of a given patient.

After steady state is achieved and in certain embodiments, less than about 2 μg of cortexolone can be detected in the patient's urine. In other embodiments, less than about 1.75 μg, less than about 1.5 μg, less than about 1.25 μg, less than about 1 μg, less than about 0.75 μg, or less than about 0.5 μg of cortexolone can be detected in the urine of a given patient. In certain embodiments, even after steady state is achieved, cortexolone cannot be detected in the urine of a given patient.

In certain embodiments, tetrahydrocortexolone can also be detected in the patient's urine. For example, in certain embodiments, less than about 150 μg of tetrahydrocortexolone can be detected in the patient's urine after initial topical application of the formulation. In other embodiments, less than about 125 μg, less than about 100 μg, less than about 75 μg, less than about 65 μg, less than about 55 μg, or about 50 μg of tetrahydrocortexolone can be detected in the urine of a given patient. . In certain embodiments, tetrahydrocortexolone cannot be detected in the urine of a given patient.

After steady state is achieved and in certain embodiments, less than about 400 μg of tetrahydrocortexolone can be detected in the patient's urine. In other embodiments, less than about 350 μg, less than about 325 μg, less than about 300 μg, less than about 225 μg, less than about 150 μg, or about 230 μg of tetrahydrocortexolone can be detected in the urine of a given patient. . In certain embodiments, even after steady state is achieved, tetrahydrocortexolone cannot be detected in the urine of a given patient.

Mode of administration

The formulations described herein can be administered according to a variety of schedules. In one embodiment, the mode of administration of the formulation may be continuous. For example, the formulation may be applied topically once daily, twice daily, three times daily, four times daily, or more as directed by the physician. In certain embodiments, formulations described herein can be applied topically once daily or twice daily. According to certain embodiments, the formulations described herein can be applied topically once daily. According to another embodiment, the formulations described herein can be applied topically twice daily.

In certain embodiments, the dosing regimen may become increasingly shorter. That is, the formulation may be applied once daily for a first period, then twice daily for a second period, then three times daily for a third period, and so on. In certain embodiments, the formulation may be applied once daily on the first day and twice daily thereafter with an appropriate duration of treatment determined by the subject's physician.

In certain embodiments, the formulation may be applied over a period of days, weeks, or months. For example, formulations may be used for up to 1, 2, 3, 4, 5, 6, or 7 days; About 2 weeks, about 3 weeks, or about 4 weeks; About 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year (i.e. about 12 months) , for about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months. Can be applied 1, 2, 3, 4, or 5 times. According to certain embodiments, the formulation may be applied once on the first day and twice daily thereafter for about 4 weeks.

In other embodiments, the dosage form is: once daily for 1 month, once daily for 2 months, once daily for 3 months, once daily for 4 months, once daily for 5 months, once daily for 6 months, 8 1 time per day for 12 months, 1 time per day for 14 months, 1 time per day for 16 months, 1 time per day for 18 months, 1 time per day for 20 months, 1 time per day for 22 months, or 24 It can be applied topically to the scalp once daily for months. In certain embodiments, the formulation may be applied topically on the scalp once daily for 6 months. In certain embodiments, the formulation may be applied topically on the scalp once daily for 12 months.

In other embodiments, the formulation lasts for about 1 month, for about 2 months; For about 3 months; For about 4 months; For about 5 months; on the scalp twice daily for about 6 months, about 8 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, about 22 months, or about 24 months. Can be applied topically. In certain embodiments, the formulation may be applied topically on the scalp twice daily for 6 months. In certain embodiments, the formulation may be applied topically on the scalp twice daily for 12 months.

In other embodiments, the formulation lasts for about 1 month, for about 2 months; For about 3 months; For about 4 months; For about 5 months; More than twice daily (for about 6 months, for about 8 months, for about 12 months, for about 14 months, for about 16 months, for about 18 months, for about 20 months, for about 22 months, or for about 24 months) That is, it can be applied as TID, QID, etc.). In certain embodiments, the formulation may be applied topically on the scalp more than twice daily (i.e., TID, QID, etc.) for 6 months. In certain embodiments, the formulation may be applied topically on the scalp more than twice daily (i.e., TID, QID, etc.) for 12 months.

In other embodiments, the mode of administration of the formulation may be periodic. For example, the formulation may first be applied in a continuous manner as described above for the desired period of time, then the application is interrupted for a period of time, such as several days, and then application of the formulation is resumed as described above. The treatment period may include one or more cycles, which may be the same or different. In certain embodiments, the treatment period may be as follows: a) the formulation is applied topically on the scalp for a period of time, such as 4 months, by continuous administration, and b) such application is applied for several days, such as 2 to 5 days. 3) topical application is continued for an additional period, such as 6 months.

The amount of cortexolone-17α-propionate that can be applied to patients in need of it can vary. In some embodiments, about 400 mg of Cortexolone-17α-propionate may be applied, or about 375 mg of Cortexolone-17α-propionate may be applied, or about 350 mg of Cortexolone-17α may be applied. -propionate may be applied, or about 325 mg of cortexolone-17α-propionate may be applied, or about 300 mg of cortexolone-17α-propionate may be applied, or about 275 mg of cortexolone-17α-propionate may be applied. Texolone-17α-propionate may be applied, or about 250 mg of cortexolone-17α-propionate may be applied, or about 225 mg of cortexolone-17α-propionate may be applied. In some embodiments, about 200 mg of Cortexolone-17α-propionate may be applied, or about 175 mg of Cortexolone-17α-propionate may be applied, or about 150 mg of Cortexolone-17α may be applied. -propionate may be applied, or about 125 mg of cortexolone-17α-propionate may be applied, or about 100 mg of cortexolone-17α-propionate may be applied, or about 75 mg of cortexolone-17α-propionate may be applied. Texolone-17α-propionate may be applied, or about 50 mg of cortexolone-17α-propionate may be applied, or about 25 mg of cortexolone-17α-propionate may be applied, or about 12.5 mg of Cortexolone-17α-propionate may be applied, or approximately 6.25 mg of Cortexolone-17α-propionate may be applied. Determination of the appropriate amount of formulation that should be administered to a given patient in a single application is within the skill of a physician of ordinary skill.

In certain embodiments, the amount of cortexolone-17α-propionate in a single application can range from about 20 mg to about 400 mg. In other embodiments, the amount of cortexolone-17α-propionate in a single application may range from about 20 mg to about 350 mg. In other embodiments, the amount of cortexolone-17α-propionate in a single application may range from about 20 mg to about 300 mg. In other embodiments, the amount of cortexolone-17α-propionate in a single application may range from about 20 mg to about 250 mg.

In certain embodiments, the amount of cortexolone-17α-propionate in a single application can range from about 20 mg to about 200 mg. In other embodiments, the amount of cortexolone-17α-propionate in a single application may range from about 20 mg to about 170 mg. In other embodiments, the amount of cortexolone-17α-propionate in a single application may range from about 20 mg to about 150 mg. In certain embodiments, the amount of cortexolone-17α-propionate in a single application can range from about 20 mg to about 100 mg. In certain embodiments, the amount of cortexolone-17α-propionate in a single application is about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg. mg, about 60 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or about 100 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 25 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 30 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 50 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 75 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 80 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 100 mg. In other embodiments, the amount of cortexolone-17α-propionate in a single application is about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117. mg, about 118 mg, about 119 mg, or about 200 mg. In another embodiment, the amount of cortexolone-17α-propionate in a single application may be about 150 mg.

By way of example only, about 50 mg of cortexolone-17α-propionate may be administered in 1 ml of one embodiment of a formulation disclosed herein, wherein the formulation contains about 5% by weight of cortexolone-17α-propionate. Contains cypionate.

In some embodiments, the formulation may be self-administered by the patient once daily or twice daily. In certain embodiments, when the formulation is in liquid form with an active agent concentration of about 5% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

In another embodiment, when the formulation is in liquid form with an active agent concentration of about 2.5% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

In another embodiment, when the formulation is in liquid form with an active agent concentration of about 3% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

In another embodiment, when the formulation is in liquid form with an active agent concentration of about 7.5% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

In another embodiment, when the formulation is in liquid form with an active agent concentration of about 8% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

In another embodiment, when the formulation is in liquid form with an active agent concentration of about 10% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

In another embodiment, when the formulation is in liquid form with an active agent concentration of about 15% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

In another embodiment, when the formulation is in liquid form with an active agent concentration of about 20% by weight, the formulation can be administered in a volume ranging from about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and in a further embodiment, from about 1 ml. It can be self-administered once daily or twice daily.

The formulations described herein can be used on any body surface in need of treatment, such as the scalp, face (e.g., eyebrows, eyelashes, upper lip, lower lip, chin, cheeks, beard area, or mustache area), arms, armpits, It may be applied to the legs, chest, abdomen, or any combination thereof. In certain embodiments, treatment is not delivered to the face. In another embodiment, the formulation may be delivered to the scalp.

Efficacy parameters

It has been surprisingly found that the pharmaceutical formulations described herein can maximize delivery of the therapeutic agent cortexolone-17α-propionate to the target site (i.e., hair follicles), thereby minimizing its systemic absorption. Accordingly, an advantage of the pharmaceutical formulations of the present invention is that they can deliver the active agent with sufficient penetration to reach the hair follicles after topical application, but without so much penetration as to be widely systemically available. This translates into a pharmacological profile characterized by efficacy in promoting hair regrowth (local activity on hair follicles) in the absence of significant adverse events, including those due to systemic antiandrogenic effects (low systemic absorption of the therapeutic agent). do.

In some embodiments, the formulations described herein provide a mean change from baseline in target area hair count of at least 8 hairs/cm 2 after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide a mean change from baseline in target area hair count of at least 9 hairs/cm 2 after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide a mean change from baseline in target area hair count of at least 10 hairs/cm 2 after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide a mean change from baseline in target area hair count of at least 11 hairs/cm 2 after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide a mean change from baseline in target area hair count of at least 12 hairs/cm 2 after 6 months of daily application or BID application.

In some embodiments, the formulations described herein provide a weighted average HGA score of 0.20 or greater after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide a weighted average HGA score of at least 0.30 after 6 months of daily application or BID application.

In some embodiments, the formulations described herein provide a weighted average HGA score of 0.40 or greater after 6 months of daily application or BID application.

In some embodiments, the formulations described herein provide a weighted average IGA score of 0.10 or greater after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide a weighted average IGA score of at least 0.20 after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide a weighted average IGA score of at least 0.30 after 6 months of daily application or BID application.

In some embodiments, the formulations described herein provide good (positive) HGA scores in at least about 10% of subjects after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide good (positive) HGA scores in at least about 20% of subjects after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide good (positive) HGA scores in at least about 30% of subjects after 6 months of daily application or BID application.

In some embodiments, the formulations described herein provide good (positive) IGA scores in at least about 10% of subjects after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide good (positive) IGA scores in at least about 20% of subjects after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide good (positive) IGA scores in at least about 30% of subjects after 6 months of daily application or BID application.

In another embodiment, the formulations described herein provide good (positive) IGA scores in at least about 40% of subjects after 6 months of daily application or BID application.

In some embodiments, the formulations described herein are effective in stimulating hair regrowth, thereby providing the TAHC, HGA score, and IGA score disclosed above, without exerting systemic anti-androgenic activity. Such formulations avoid side effects due to systemic antiandrogenic effects. These side effects include, but are not limited to, reduced sexual desire, erectile dysfunction (erectile dysfunction), ejaculation difficulties, and reduced ejaculate volume.

storage stability

Storage stability is an important metric for pharmaceutical products. In general, greater stability means that a given formulation is easier to both transport and store, increasing the likelihood that it will be stocked in pharmacies and patients will not have to worry about special storage instructions. The formulations described herein can be stored for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 2 years—each at room temperature. or at refrigerated temperatures - has a desirable stability profile that allows for storage of the final formulation.

For example, one of the major degradation pathways for cortexolone-17α-propionate is cortexolone-21-propionate (17a-hydroxy-21-propionyloxy-pregna-4-en-3 ,20-dione) is transesterified:

It has now been surprisingly discovered that this degradation process can be significantly slowed by maintaining the formulations disclosed herein at a pH of less than about 6, and in certain embodiments, about 5, from about 4 to about 5, or about 4. In certain embodiments, the pH may be 4. Appropriate pH can be obtained through addition of an appropriate amount of pH adjusting agent.

Acceptable pH modifiers include pharmaceutically acceptable organic and inorganic acids known to those skilled in the art. Examples of such acids include, but are not limited to: 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; L-ascorbic acid; L-aspartic acid; benzenesulfonic acid; benzoic acid; (+)-camphor acid; (+)-Camphor-10-sulfonic acid; Capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; Sinnamsan; citric acid; cyclamic acid; dodecyl sulfate; Ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; D-Glucoheptonic acid; D-gluconic acid; D-glucuronic acid; glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; Hydrochloric acid; isobutyric acid; lactic acid; lactobionic acid; lauric acid; maleic acid; L-malic acid; malonic acid; mandelic acid; methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; Proprionic acid; L-pyroglutamic acid; salicylic acid; sebacic acid; stearic acid; Succinic acid; Sulfuric acid; L-tartaric acid; thiocyanic acid; p-toluenesulfonic acid; and undecylenic acid. In certain embodiments, the pH adjusting agent can be citric acid.

In certain embodiments, the formulations described herein may have less than about 5% by weight cortexolone-21-propionate or other degradation products after storage for a period of about 24 months, at room temperature or refrigerated temperature.

Although pH may be important for stability, it has also been discovered that the addition of antioxidants to the formulation can help maintain storage stability. Antioxidants may be present in addition to pH modifiers. However, in some embodiments, the pH modifier may be substantially or completely absent. Antioxidants may be present in amounts specified elsewhere herein.

Formulations containing cortexolone-17α-propionate as disclosed herein provide an acceptable pharmacokinetic profile of both cortexolone 17α-propionate and/or its metabolites, minimizing systemic exposure. It was surprisingly found to provide a therapeutically effective amount of therapeutic agent to the scalp and/or skin. Without wishing to be bound by any particular theory, it is believed that the formulations disclosed herein deliver therapeutic agents to the dermis while minimizing deeper penetration due to the properties of the formulations disclosed herein. This effect is demonstrated in the Franz cell data reported in Examples 6 and 7 below.

By virtue of such favorable pharmacokinetic profile, high therapeutic levels of the therapeutic agent at the target site and low levels in the systemic circulation, formulations as disclosed herein are efficacious in treating alopecia without significant adverse events.

Moreover, the formulations disclosed herein have an optimal stability profile, allowing storage of the final product for at least 2 years (when stored at refrigerated temperature or room temperature, as specified by the Pharmaceutical Guideline). .

Example

The formulations described herein are now described in further detail with reference to the following examples. These examples are provided for illustrative purposes only, and the embodiments described herein should in no way be construed as limited to these examples. Rather, these embodiments should be construed to include any and all modifications that become apparent as a result of the teachings provided herein.

Example 1: Evaluation of cortexolone-17α-propionate solubility.

To create a 5% w/v solution of cortexolone-17α-propionate, 5 g of cortexolone-17α-propionate was added to 100 ml of each solvent or solvent mixture shown in Table 1 below. . In the examples in Table 1, ethanol refers to Ethanol 96°.

[Table 1]

As can be seen from the data in Table 1, water is an unsuitable solvent for cortexolone-17α-propionate when used alone or in a binary mixture. TRANSCUTOL® increased the solubility of the therapeutic agent in each mixture using it. Likewise, although ethanol has been found to readily solubilize cortexolone-17α-propionate, it cannot be used alone due to its abuse potential as well as possible burning after topical application.

Example 2: cortexolone - 17α - Propionate Evaluation of pH on solubility.

In a suitable vessel, under stirring, 50 g of cortexolone-17α-propionate were dissolved in a mixture of TRANSCUTOL® (461 g) and ethanol 96° (200 g). After complete dissolution of cortexolone-17α-propionate, water (283 g) was added slowly. Finally, polysorbate 80 (5 g) and alpha tocopherol (vitamin E) (1 g) were added to the formulation. The neutral pH of this formulation was determined to be approximately 5.1 using a standard pH electrode.

The formulation was then divided into three equal batches, each weighing approximately 300 g. Citric acid was added to the first batch to lower the pH to about 4. Sodium citrate was added to the second batch to increase the pH to about 6. A third batch with a neutral pH of about 5.1 was used as a control. Three batches were then subjected to a short-term stability study at 30°C and the results are shown in Table 2.

[Table 2]

The data clearly show that the production of cortexolone-21-propionate is significantly reduced at a pH of about 4.

Example 3: Antioxidant evaluation

Containing 5% by weight of cortexolone-17α-propionate in a mixture of TRANSCUTOL®, propylene glycol, and ethanol (96°) in a weight ratio of approximately 1:1:1, with an additional 0.1% by weight of polysorbate 80. To the formulation containing, the following antioxidants were added: alpha tocopherol (vitamin E) 0.3% by weight; 0.01% by weight of butylated hydroxyanisole (BHA), or 0.5% by weight of ascorbyl palmitate. These three formulations were then studied under short-term stability conditions. The results are shown in Table 3.

[Table 3]

Ascorbyl palmitate gave the least amount of total degradation products.

Example 4a: Anhydrous 5% w/w solution

After solubilizing the therapeutic agent in a mixture of solvents, a 5% by weight (w/w) solution of cortexolone-17α-propionate having the ingredients shown in Table 4 below was added to the antioxidant (ascorbyl palmitate) and emulsifier ( It was prepared by adding polysorbate 80).

[Table 4]

This formulation provided the stability profile (40°C/75% RH) shown in Table 5.

[Table 5]

Example 4b: Anhydrous 5% w/v solution

After solubilizing the therapeutic agent in a mixture of solvents, a 5% (w/v) solution of cortexolone-17α-propionate with the ingredients shown in Table 6 below was added to the antioxidant (ascorbyl palmitate) and emulsifier (poly It was prepared by adding sorbate 80).

[Table 6]

Example 5: Anhydrous 5% w/w solution

Formulations of cortexolone-17α-propionate with the ingredients shown in Table 7 below were prepared by solubilizing the therapeutic agent in a mixture of solvents and then adding antioxidants and emulsifiers.

[Table 7]

The stability of this formulation at 40°C/75% RH is shown in Table 8.

[Table 8]

Based on the impurity profile, the formulation prepared in Example 4a is more stable than the aqueous formulation in Example 5.

Example 6: Clinical evaluation

The formulation described in Example 4b was studied in clinical trials to evaluate its pharmacokinetic profile, safety, and tolerability. According to the study protocol, 1 ml of formulation (corresponding to 50 mg of cortexolone-17α-propionate) is administered to the area of the scalp where alopecia is affected once daily on study day 1, and then on study day 2 thereafter. It was applied twice daily from day 28 to day 28. The formulations provided pharmacokinetic profiles shown in Tables 9 and 10 and excretion data shown in Table 11. Statistical analyzes were performed using SAS® version 9.1.3, Service Pack 4 for Windows and Phoenix WinNonLin 6.3 from Pharsight Corporation, USA.

[Table 9]

[Table 10]

[Table 11]

Example 7: Franz Cell Diffusion Test 1

In an in vitro study, the skin penetration potential of cortexolone-17α-propionate was compared to cyproterone acetate using standard Franz cells. According to the protocol, 300 mg of each test formulation was applied as a saturated solution at concentrations ranging from 0.7 to 1 weight (w/w) on an exposed skin area of 2.54 cm 2 . Receiving chamber volumes ranged from 4.75 ml to 6.4 ml of phosphate buffered saline/fetal bovine serum (2:1) containing penicillin/streptomycin according to standard protocols and were maintained at a temperature of 32°C +/- 1°C. Agitation was maintained at 300 rpm.

The experiment was repeated three times and performed for 48 hours. Fractions of 100 μl were withdrawn at 5 to 7 time points during the 48 hour test period. For analysis, a 100 μl fraction was taken out and replaced with an equal volume of fresh receiver fluid. At the end of the experiment, the skin was obtained from Franz Cell and the stratum corneum of the skin was removed by tape stripping (20x) with a transparent adhesive tape (Kores, Spain).

Stripping analytes were analyzed by dissolving them in a 9:1 mixture of propylene glycol:oleyl alcohol. The resulting mixture was analyzed for the concentration of cyproterone acetate and cortexolone-17α-propionate, and the results are provided in Table 12 below.

[Table 12]

As can be seen from the data, cortexolone-17α-propionate penetrates the skin approximately 3 times as much as cyproterone acetate and has a penetration rate approximately 10 times greater than cyproterone acetate.

Example 8: Franz Cell Diffusion Test 2

Next, the concentration of the active agent in the receiving fluid was measured using a system substantially identical to that in Example 7. Using three human donor skin samples, the transmittance expressed as cumulative transmittance (μg/cm2) is presented in Table 13. This experiment compared the anhydrous solution of Example 4a with the aqueous solution of Example 5. Each contained the same amount of cortexolone-17α-propionate (5%).

[Table 13]

As evident from the data in Table 13, water in the formulation can reduce the penetration of cortexolone-17α-propionate into the skin.

Example 9: Phase 2 clinical study in men with androgenetic alopecia (AGA)

The formulation described in Example 4b was studied in a multicenter, randomized, double-blind, phase 2 controlled study. In this study, the formulation of Example 4b (5% solution of cortexolone-17α-propionate) was compared to the vehicle solution as a placebo. Both formulations containing active agents and vehicle formulations were applied twice daily for 26 weeks in men with androgenic alopecia (AGA). This study followed Good Clinical Practice (GCP) for Clinical Research Studies (CRS).

purpose

The primary objective of this study was to determine the effectiveness of topical application of cortexolone-17α-propionate 5% solution (with the composition of Example 4b) (twice daily) and vehicle solution (twice daily) in men with AGA. The goal was to compare safety and efficacy.

research subject

Subjects were 18 to 50 years of age, with a modified Hamilton-Norwood Scale rating of III vertex to V (IIIv, IV, V), with mild to moderate inflammation in the temporal and parietal regions of the scalp. had AGA, and hair loss was ongoing.

therapy

Subjects received either a 5% solution of cortexolone-17α-propionate or a vehicle control solution depending on allocation group, and the provided formulation was applied to the bald areas of the scalp (crown and temples) twice daily for 6 months.

visit schedule

Subjects had visits at baseline (Visit 2), at 1 month (Visit 3), at 2 months (Visit 4), at 4 months (Visit 5), and at 6 months (Visit 6). Subject screening (Visit 1) was conducted within 2 weeks of the baseline visit (Visit 2). All measurements of efficacy and safety endpoints were performed at all study visits except Visits 2 and 3, where only local tolerability assessment (LTA) and adverse events (AEs) were assessed. It was carried out.

research measurements

Table 14 reports study measurements for hair loss classification, efficacy endpoints, and safety endpoints.

[Table 14]

Table 15 reports study endpoints categorized as efficacy or safety endpoints.

[Table 15]

The Intent-To-Treat (ITT) population included fully randomized subjects who received at least one application of study drug and was the primary population used for safety assessments. The per-protocol (PP) population is a subset of the ITT population that completed the study and had no major protocol deviations, and was considered the primary population for statistical analysis of efficacy endpoints. At the end of this study, the ITT was subdivided into study groups as follows: 31 subjects in the cortexolone-17α-propionate solution 5% arm and 33 subjects in the vehicle solution arm. At the end of this study, the PP population was subdivided into study groups as follows: 23 subjects in the cortexolone-17α-propionate solution 5% test group and 25 subjects in the vehicle solution test group.

Change from baseline in target area hair count (TAHC) of non-down hair at Month 6 (primary efficacy endpoint)

Target area hair counts (TAHC) of non-down hair were calculated using digital image analysis from standardized macro photographs collected at months 2, 4, and 6. Table 16 records the change from baseline in TAHC of non-down hair at month 6 for the PP group: These values are the baseline number of non-down hair in a 1 cm area of the scalp after 6 months of treatment. refers to a change from .

[Table 16]

As demonstrated in the above data, cortexolone-17α-propionate solution (5%) had a greater change from baseline in TAHC of non-down hair compared to vehicle at month 6. Cortexolone-17α-propionate solution 5% (according to Example 4b) had a mean change from baseline in TAHC of non-down hair, compared to vehicle, which had a mean change from baseline of 2.9 in TAHC of non-down hair. had a larger mean change from baseline (12.7).

Hair growth assessment at month 6

Subjects used a baseline normalized global photograph of their scalp and compared it side-by-side with a “real-time” standardized global photograph at month 6 to provide a comparative assessment of HGA. Subjects assessed hair growth using a 7-point scale. Figure 1 shows the HGA frequency distribution for the two treatment groups at month 6. In this figure, negative HGA scores (-3, -2, and -1) were grouped into an overall HGA score named “not good”; A score of 0 was termed “no change” and positive scores (+1, +2 and +3) were grouped into an overall HGA score termed “good”. HGA scores for the PP group at month 6 are reported in Table 17.

[Table 17]

The proportion of subjects rated as having good scalp hair growth was directionally greater with the cortexolone-17α-propionate solution (5%) (39%) compared to vehicle (16%). Among subjects with good hair growth, the proportion of subjects whose hair growth was rated as greatly increased (+3), moderately increased (+2), and slightly increased (+1) was They were 4%, 13%, and 22% for the 5% nate solution, respectively, and 0%, 8%, and 8% for the vehicle, respectively. The weighted average of HGA at month 6 for both treatment groups (PP group) was calculated as follows: Cortexolone-17α-propionate solution 5% had an increase in HGA at month 6 (0.30) compared to placebo (-0.24). ) had a higher HGA weighted average.

This data demonstrates that subjects in the cortexolone-17α-propionate solution 5% group had a greater magnitude of improvement compared to the vehicle solution.

Hair Growth Index (HGI) at Months 6

Subjects used a baseline normalized global photograph of their scalp and compared it side-by-side with a “real-time” standardized global photograph at month 6 to provide a comparative assessment of HGI. Hair growth was compared from baseline by three questions on the health outcomes questionnaire. The proportion of subjects rated as having good scalp hair growth was 5% for cortexolone-17α-propionate solution (Q1: 39%, Q2: 35%, and Q3: 43%).

Hair Growth Satisfaction Scale (HGSS) at Month 6

Subjects used a baseline normalized global photograph of their scalp and compared it side-by-side with a “real-time” standardized global photograph at month 6 to provide a comparative assessment of HSS. Hair appearance/growth was compared from baseline using 5 questions. The proportion of subjects who were satisfied with scalp hair growth was greater with the 5% Cortexolone-17α-propionate solution compared to the vehicle solution. For questions numbers 1 to 5 (Q1 to Q5), the proportion of subjects rated as having good scalp hair growth (scores +1, +2 and +3) compared to the vehicle solution (Q1/Q3: 8%, Q2/Q4) /Q5: 20%), it was higher in the case of cortexolone-17α-propionate solution 5% (Q1: 38%, Q2 to Q5: 30%). For the cortexolone-17α-propionate 5% solution, subjects were not 'very dissatisfied' (score -3) with any of the HGSS questions at month 6, while for vehicle, at month 6. In all HGSS questions, some subjects responded that they were very dissatisfied.

Investigator's Global Assessment (IGA) at Month 6

At Month 6, researchers used a standardized global photograph of the subject's scalp taken at baseline and compared it to a real-time assessment of the subject's scalp hair growth using a 7-point scale. Figure 2 shows the frequency distribution of IGA for the two treatment groups (one for cortexolone-17α-propionate solution and one for vehicle solution) at Month 6. In Figure 2, negative IGA scores (-3, -2, and -1) are grouped into an overall IGA score named “not good”; A score of 0 is termed “no change” and positive scores (+1, +2 and +3) are grouped into an overall IGA score termed “good”. IGA scores for the PP group at month 6 are reported in Table 18.

[Table 18]

The proportion of subjects with good IGA scores (scores +1, +2, and +3) was higher in the cortexolone-17α-propionate solution 5% group (43%) than in the vehicle group (36%), and good The proportion of subjects with negative IGA scores (scores -1, -2 and -3) was lower for cortexolone-17α-propionate (9%) compared to vehicle (20%). The weighted average of IGA at month 6 for both treatment groups (PP group) was calculated as follows: Cortexolone-17α-propionate solution 5% resulted in an increase in IGA at month 6 (0.43) compared to placebo (0.12). had a higher IGA weighted average.

This data demonstrates that subjects in the cortexolone-17α-propionate solution 5% group had a greater magnitude of improvement compared to the vehicle solution.

Assessment of local tolerability and adverse events

A local tolerability assessment analysis was performed on all subjects who applied the test article at least once (ITT group). The incidence of each symptom in LTA was low throughout the study period and generally similar between treatment groups. Of the reported signs of local tolerance, most signs were minimal to mild in severity and (in descending order of incidence) pruritus, exfoliation, erythema, folliculitis, hyperpigmentation, and hypopigmentation were present after treatment.

The incidence of adverse events (AEs) was similar between treatment groups, with most events typically mild in severity and not related to the test subject. In the cortexolone-17α-propionate solution 5% group, AEs occurred in 18/31 subjects (58.1%), while in the vehicle group, AEs occurred in 17/33 subjects (51.5%). Most AEs were mild. The four AEs in the vehicle group were rated as moderate, of which only one (headache) was possibly related to the test article. No serious AEs occurred in the cortexolone-17α-propionate group.

Importantly, adverse events that may be attributable to systemic antiandrogenic effects (e.g., reduced libido, erectile dysfunction, and/or ejaculatory dysfunction) are unlikely to occur after 6 months of cortexolone-17α-propionate solution 5%. It did not occur in any patient treated with .

conclusion

This study was a phase II POC study with limited number of subjects and did not seek to demonstrate statistically significant differences between study groups; Nevertheless, this study demonstrated a significant improvement in hair growth with 5% solution of Cortexolone 17α-propionate compared to vehicle: Cortexolone 17α-Propionate in the PP group at 6 months. (12.7) had a superior change from baseline in target area hair count (TAHC) for non-down hair compared to vehicle (2.9). Results of the subjects' hair growth assessment questionnaire (the study's other primary efficacy endpoint) were consistent with the quantitative TAHC measurements, with a higher proportion of subjects graded as having good scalp hair growth with Cortexolone compared to vehicle (16%). It was greater for 17α-propionate (39%); Among subjects rated as having good scalp hair growth, Cortexolone 17α-propionate tended to have a greater magnitude of improvement compared to vehicle. The results of the secondary endpoints were generally consistent with the results of the primary endpoint.

Example 10: 15% (w/v) solution

After solubilizing the therapeutic agent in a mixture of solvents, a 15% (w/v) solution of cortexolone-17α-propionate with the ingredients shown in Table 19 below was added to the mixture of an antioxidant (ascorbyl palmitate) and an emulsifier (polymer). It was prepared by adding sorbate 80).

[Table 19]

Example 11: Comparison of the effectiveness of the formulation of Example 4b and commercially available finasteride 1 mg tablets (PROPECIA®)

As reported in Example 9, based on the results of finasteride 1 mg tablets (PROPECIA®) described in two phase III clinical studies published online by the U.S. Food and Drug Administration (FDA) (according to Example 4b) ) Mean change from baseline in TAHC of non-down hair at 6 months for cortexolone-17α-propionate solution 5% for finasteride 1 mg tablets (brand name Propecia®) administered orally once daily It can be concluded that the mean change from baseline in TAHC of non-down hair at 6 months was very similar to that observed in two phase III clinical trials. Table 20 below reports the change from baseline in TAHC at Month 6 in two finasteride studies (data from the active agent finasteride group) as described in the NDA for PROPECIA® published online by the FDA:

[Table 20]

In the two finasteride studies, the target area was a 1 inch diameter circle, equivalent to 5.1 cm2. Changes from baseline in TAHC at 6 months obtained in these finasteride studies and with cortexolone-17α-propionate in the study of Example 9 of the invention (where the target area was 1 cm 2 ). To compare the change from baseline in TAHC at month 6, the original finasteride data were recalculated taking into account the difference between the total surface area of these target areas (i.e., dividing the values by 5.1), which are shown in Table 21. As shown.

[Table 21]

Therefore, the change from baseline in TAHC at 6 months on finasteride was: 13.6 for Study 087, 11.5 for Study 089, and 12.2 for the two studies combined. It is clear that these values are almost identical to the change from baseline in TAHC at month 6 in the PP population for the 5% solution of cortexolone-17α-propionate prepared according to Example 4b (12.7). As discussed above, at month 6, the efficacy of finasteride 1 mg tablets administered orally once daily and cortexolone-17α-propio administered topically twice daily on the patients' scalp, measured as hair growth, at month 6. The efficacy of 5% Nate solution was comparable.

Phrases or terms used herein are for the purpose of description and are not limiting. Therefore, terms and/or phrases herein should be interpreted by those skilled in the art in light of the teachings and guidance herein.

The scope and scope of the invention should not be limited by any of the above-described exemplary embodiments, but should be limited only by the following claims and their equivalents.

All patents, patent applications, and other references mentioned or referenced in this application are hereby incorporated by reference in their entirety.

Claims (97)

A subject in need of treatment of alopecia, comprising 5% to 15% by weight of cortexolone-17α-propionate and one or more pharmaceutically acceptable solvents, being anhydrous and containing less than 5% by weight of water. A topical pharmaceutical formulation for treating alopecia, wherein the one or more pharmaceutically acceptable solvents are selected from C ₁ -C ₇ alcohols, polyol ethers, polyols, or mixtures thereof, and wherein the cortexolone-17α-propionate is a topical pharmaceutical formulation that is completely solubilized in the formulation. The topical pharmaceutical formulation of claim 1 comprising 15%, 10%, 8%, 7.5%, 5.5%, or 5% by weight of cortexolone-17α-propionate. The topical pharmaceutical formulation according to claim 1 or 2, which is in liquid or semi-solid formulation. The topical pharmaceutical formulation according to claim 1 or 2, which is a solution, suspension, emulsion, microemulsion, cream, gel, foam, or ointment. 3. The method of claim 1 or 2, wherein the mean C _max of cortexolone-17α-propionate is less than 3 ng/ml after topical application of a single dose comprising 50 mg of cortexolone-17α-propionate. A topical pharmaceutical formulation providing. 3. The topical pharmaceutical formulation of claim 1 or 2, which provides a mean T _max of cortexolone-17α-propionate of less than 20 hours, less than 15 hours, or less than 12 hours after administration of a single topical dose. 3. The method according to claim 1 or 2, wherein the dose is less than 25 (ng*h)/ml, less than 20 (ng*h)/ml after topical administration of a single dose comprising 50 mg of cortexolone-17α-propionate. , or a topical pharmaceutical formulation providing a mean AUC _0-t of 15.69 ± 4.3 (ng*h)/ml. 3. The method according to claim 1 or 2, wherein the mean stability of cortexolone-17α-propionate is 3.82 ± 1.34 ng/ml after topical administration of a single dose comprising 50 mg of cortexolone-17α-propionate. -Topical pharmaceutical formulations providing steady-state C _max . 3. The mean steady-state time of cortexolone-17α-propionate according to claim 1 or 2 at 4.38 ± 1.96 hours after topical administration of a single dose comprising 50 mg of cortexolone-17α-propionate. Topical pharmaceutical formulation providing T _max . 3. The method of claim 1 or 2, wherein a mean steady-state AUC _0-t of 37.37 ± 12.36 (ng*h)/ml following topical administration of a single dose comprising 50 mg of cortexolone-17α-propionate. A topical pharmaceutical formulation providing. The method of claim 1 or 2, wherein the alopecia is androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, traction alopecia, or any combination thereof. The topical pharmaceutical formulation according to claim 1 or 2, wherein the alopecia is androgenetic alopecia. 3. The topical pharmaceutical formulation of claim 1 or 2, further comprising at least one antioxidant, at least one emulsifier, or a combination thereof. The topical pharmaceutical formulation according to claim 1 or 2, which is administered topically once or twice daily. 3. The topical pharmaceutical formulation of claim 1 or 2, wherein the formulation is liquid. Topical pharmaceutical formulation according to claim 1 or 2, wherein 0.2 to 2.0 ml is administered during each application. A topical pharmaceutical formulation comprising cortexolone-17α-propionate at a concentration of 5% to 15% by weight and one or more pharmaceutically acceptable solvents, the formulation being anhydrous and containing less than 5% water by weight, comprising: A topical pharmaceutical formulation, wherein the pharmaceutically acceptable solvent is selected from C ₁ -C ₇ alcohols, polyol ethers, polyols, or mixtures thereof, and wherein the cortexolone-17α-propionate is fully solubilized in the formulation. 18. The topical pharmaceutical formulation of claim 17 comprising cortexolone-17α-propionate at a concentration of 15%, 10%, 8%, 7.5%, 5.5%, or 5% by weight. 19. Topical pharmaceutical formulation according to claim 17 or 18, which is in liquid or semi-solid formulation. 20. The topical pharmaceutical formulation of claim 19, wherein the liquid or semi-solid formulation is a solution, suspension, emulsion, microemulsion, cream, gel, foam, or ointment. 20. The topical pharmaceutical formulation of claim 19, which is a solution. 19. The method of claims 17 or 18, wherein upon application of an amount of said formulation comprising 50 mg of cortexolone-17α-propionate the average of cortexolone-17α-propionate is less than 7.0 ng/ml. Topical pharmaceutical formulations providing steady-state C _max . 19. The method according to claim 17 or 18, wherein upon application of an amount of said formulation comprising 50 mg of cortexolone-17α-propionate, the average stability of cortexolone-17α-propionate is less than 8.0 hours. Topical pharmaceutical formulation providing condition T _max . 19. The method of claims 17 or 18, wherein upon application of an amount of said formulation comprising 50 mg of cortexolone-17α-propionate, the amount of cortexolone-17α-propionate is less than 64.1 (ng*h)/ml. A topical pharmaceutical formulation providing the AUC _τ of cypionate. 18. The topical pharmaceutical formulation of claim 17, wherein the C ₁ -C ₇ alcohol is ethanol, isopropanol, or methanol. 26. The topical pharmaceutical formulation of claim 25, wherein the C ₁ -C ₇ alcohol is ethanol. 27. The topical pharmaceutical formulation of claim 26, wherein the ethanol is 96°. 28. The topical pharmaceutical formulation of claim 27, wherein the ethanol is absolute ethanol. 18. The topical pharmaceutical formulation of claim 17, wherein the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerol, and hexanetriol. 30. The topical pharmaceutical formulation of claim 29, wherein the polyol is propylene glycol. 18. The topical pharmaceutical formulation of claim 17, wherein the polyol ether is selected from the group consisting of polypropylene glycol, polyethylene glycol, polyethylene-polypropylene triblock copolymer, dipropylene glycol, and diethylene glycol monoethyl ether. 32. The topical pharmaceutical formulation of claim 31, wherein the polyol ether is diethylene glycol monoethyl ether. 18. The topical pharmaceutical formulation of claim 17, wherein the polyol is propylene glycol, the polyol ether is diethylene glycol monoethyl ether, and the C ₁ -C ₇ alcohol is ethanol. 18. The topical pharmaceutical formulation of claim 17 containing less than 3% water by weight. 19. Topical pharmaceutical formulation according to claim 17 or 18, further comprising an emulsifier. 19. The topical pharmaceutical formulation of claim 17 or 18, further comprising an antioxidant. 37. The method of claim 36, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alpha tocopherol, and propyl gallate. A topical pharmaceutical formulation that is. 38. The topical pharmaceutical formulation of claim 37, wherein the antioxidant is ascorbyl palmitate. 36. The method of claim 35, wherein the emulsifier is PEG-15 hydroxystearate (also known as polyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40 oleate, poly Sorbate 20, Polysorbate 60, Polysorbate 80, PEG-20 Cetostearyl Ether, Polyoxyl 25 Cetostearyl, Cetomacrogol 1000, Sorbitan Monolaurate, Sorbitan Monopalmitate, Sorbitan Monooleum ate, propylene glycol esters of fatty acids, polyglycerol esters of fatty acids, polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, caprylocapryl polyoxyl-8 glyceride; A topical pharmaceutical formulation selected from the group consisting of caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, oleoyl polyoxylglyceride, and any combinations thereof. 40. The topical pharmaceutical formulation of claim 39, wherein the emulsifier is polysorbate 80. 3. The topical pharmaceutical method of claim 1 or 2, wherein topical administration of said formulation twice daily for at least 6 months achieves hair growth comparable to that observed upon administration of oral finasteride for the same period of time. Formulation. 42. The method of claim 41, wherein topical administration provides a reduced incidence of adverse effects selected from the group consisting of reduced sexual desire, erectile dysfunction (erectile dysfunction), ejaculatory dysfunction, and reduced ejaculate volume. Pharmaceutical formulation. 3. The method of claim 1 or 2, wherein topical administration of said formulation for at least 6 months achieves a mean change from baseline in non-downy target area hair count (TAHC) of 12.7 compared to vehicle. Phosphorus topical pharmaceutical formulation. The topical pharmaceutical formulation of claim 1 or 2, wherein topical administration of the formulation for at least 6 months achieves a Weighted Average Hair Growth Assessment (HGA) score of 0.30 compared to vehicle. The topical pharmaceutical formulation of claim 1 or 2, wherein topical administration of the formulation for at least 6 months achieves a weighted average Investigator's Global Assessment (IGA) score of 0.43 compared to vehicle. The topical pharmaceutical formulation according to claim 1 or 2, wherein topical administration of the formulation for at least 6 months is free from systemic antiandrogenic side effects. The topical pharmaceutical formulation of claim 1 or 2, wherein topical administration of the formulation provides:
a) Mean change from baseline in target area hair count of 9 hairs/cm 2 or more after 6 months of daily application or BID application; or
b) mean change from baseline in target area hair count of 10 hairs/cm 2 or more after 6 months of daily application or BID application; or
c) mean change from baseline in target area hair count of 11 hairs/cm 2 or more after 6 months of daily or BID application; or
d) mean change from baseline in target area hair count of 12 hairs/cm 2 or more after 6 months of daily or BID application; or
e) Weighted average HGA score of 0.20 or greater after 6 months of daily application or BID application; or
f) Weighted average HGA score of 0.30 or greater after 6 months of daily application or BID application; or
g) Weighted average HGA score of 0.40 or greater after 6 months of daily application or BID application; or
h) Weighted average IGA score of 0.10 or more after 6 months of daily application or BID application; or
i) Weighted average IGA score of 0.20 or more after 6 months of daily application or BID application; or
j) Weighted average IGA score of 0.30 or more after 6 months of daily application or BID application; or
k) Good (positive) HGA score in at least 10% of subjects after 6 months of daily application or BID application; or
l) Good (positive) HGA score in at least 20% of subjects after 6 months of daily application or BID application; or
m) good (positive) HGA score in at least 30% of subjects after 6 months of daily application or BID application; or
n) Good (positive) IGA score in at least 10% of subjects after 6 months of daily application or BID application; or
o) Good (positive) IGA score in at least 20% of subjects after 6 months of daily application or BID application; or
p) Good (positive) IGA score in at least 30% of subjects after 6 months of daily application or BID application; or
q) Good (positive) IGA score in at least 40% of subjects after 6 months of daily application or BID application. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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